Anti-dsDNA IgG has been implicated in the pathogenesis of SLE. Using normal mice bearing transgene encoding either IgG2a or IgM anti-DNA antibodies, we will address in this proposal 1) whether the normal immune system can tolerize B cells secreting these autoreactive antibodies, 2) the stage of maturation of B cells (expressing mIgM or mIgG) which can be tolerized, 3) if sustained high levels of expression of transgenes encoding a pathogenic IgG2a anti-DNA in normal mice can induce lupus nephritis, 4) if MHC backgrounds can influence the levels of transgene expression and if that is mediated by T cells selected by MHC molecules, 5) if T cells play a role in regulating transgene expression, and 6) whether peptides that activate those T cells are derived from the transgenic Ig molecules. Results from these studies will help us understand normal mechanisms inducing B cell tolerance and the defects in immunoregulation in lupus individuals. This proposal fits the theme of the program project by studying MHC/peptide/T cell interactions which results in regulation of transgene expression. We will use both the peptide synthesis and FACS scan core facilities.